Drug Resistant Tuberculosis: An Overview

July 14, 2014, Pokhara, Nepal Dr. Sharat Chandra Verma Chief Consultant Chest Physician National TB Centre Nepal

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Some definitions

• • Multi-Drug Resistant (MDR) TB: MDR-TB is defined as TB caused by bacteria resistance to isoniazid and rifampicin, with or without resistance to other first line drugs (FLD).

Extensive Drug Resistant (XDR) TB: XDR-TB is caused by bacteria that are resistant to rifampicin and isoniazid as well as resistant to any one of the fluoroquinolones (e.g. ofloxacin and moxifloxacin) and to at least one of the injectable second-line drugs (capreomycin, kanamycin or amikacin).

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Why is MDR-TB a problem?

• • • • Possibility of resistance to all major anti-TB drugs Treatable, but requires extensive therapy: up to 2 yrs of treatment Expensive Treatment could be toxic to patients /fli6«o Ifo/f]u sfo{qmd National Tuberculosis Center

How is DR-TB transmitted?

• TB bacilli with different levels of resistance spread in the same way and with the same risk of infection as fully drug susceptible strains.

– Person-to-person through inhalation of droplet nucleii – Infected person usually coughs or sneezes and projected infected droplet nucleii into the air /fli6«o Ifo/f]u sfo{qmd National Tuberculosis Center

Pathogenesis of Drug Resistance

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Frequency of Resistance Mutations

INH = 1 in 10 6 RIF = 1 in 10 8 EMB = 1 in 10 6 Strep = 1 in 10 6 INH + RIF = 1 in 10 14 /fli6«o Ifo/f]u sfo{qmd National Tuberculosis Center

Development of Drug Resistance

Multiple Drugs vs. Monotherapy 1

INH RIF P ZA

2

R I P INH I I I I I I

3 National Tuberculosis Center

Development of Drug Resistance (2)

Further acquired resistance after single drug added

I I I I I I INH I I I I I I I I I I I IR IP I I I INH RIF IR IR IR IR IR IR IR IR IR IR IR IR IR IRP

National Tuberculosis Center

Unintended Monotherapy and Resistance

0 5 7 9 Months of Rx INH RIF Smear EMB Culture Susceptibility INH RIF EMB

+ +

R* S* S*

+ + + + + +

R R S R R S R R R

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Factors that Lead to Drug Resistance

• • • Causes of inadequate treatment: Patient-related factors Healthcare provider-related factors Healthcare system-related factors /fli6«o Ifo/f]u sfo{qmd National Tuberculosis Center

Factors that Lead to Drug Resistance

• Patient-related factors: Non-adherence, default • Malabsorption of drugs • Adverse drug reactions • • Lack of information, transportation, money • Social barriers to treatment adherence National Tuberculosis Center

Factors that Lead to Drug Resistance

• • • • •

Healthcare provider-related factors:

Inadequate initial treatment regimen: Wrong combination or doses, guideline noncompliance Treatment “in the dark” for retreatment cases: no drug susceptibility testing available, or results delayed Clinical errors: Adding a single drug to a failing regimen Lack of proper monitoring National Tuberculosis Center

Factors that Lead to Drug Resistance

•

Healthcare programme-related factors:

Unavailability of drugs (stock-outs or delivery disruptions) • Poor drug quality, poor storage conditions • Poorly organized or under-funded TB-control programmes • Inappropriate or no guidelines • Lack of appropriate or timely laboratory testing /fli6«o Ifo/f]u sfo{qmd National Tuberculosis Center

Epidemiology

• In practice, MDR-TB develops either because the person is infected initially with a: – Drug-resistant strain (primary), or – Susceptible strain that becomes resistant (secondary) /fli6«o Ifo/f]u sfo{qmd National Tuberculosis Center

Epidemiology cont.

• Reasons for secondary resistance are numerous and complex: – Wrong drugs used in an improper way – Failure to assess drug susceptibility patterns of the organism – A large bacterial load, especially in the case of cavitation – Poor adherence to the treatment regimen /fli6«o Ifo/f]u sfo{qmd National Tuberculosis Center

Epidemiology cont.

• TB (including MDR-TB) and HIV co-infections are relatively common globally and each condition adversely affects the other.

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MDR-TB notification and enrolment

MDR cases reported vs estimated among notified TB, 2012: WHO 2013

WHO Region

African American East Med.

European S-E Asian West Pacific

Global Estimated

38,000 7,100 18,000

2012 Reported

18,129 2,967 2,236

Ratio

48% 42% 12% 74,000 90,000 36,708 19,202 50% 21% 74,000 4,473 6%

300,000 83,715

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28%

National Tuberculosis Center

XDR-TB

• • In 2006, the first reports of extensively drug resistant tuberculosis (XDR-TB) began to appear.

About 9.6% (8.1-11.2%) of MDR-TB cases in countries with representative surveillance data have XDR-TB. By October 2013, 92 countries had reported one or more XDR-TB cases. (WHO Report 2013) /fli6«o Ifo/f]u sfo{qmd National Tuberculosis Center

Development of extensive drug resistance in Multi-Drug resistant tuberculosis patients • • XDR-TB emerges like MDR-TB through mismanagement of treatment.

It is however believed that many cases of XDR TB are never diagnosed due to a lack of laboratory capacity to test for resistance to second line drugs.

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Clinical Manifestations

• • MDR-TB are not clinically distinguishable from drug-susceptible TB at the outset.

Signs, symptoms, and radiological findings are similar initially to drug-susceptible TB.

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Reasons to suspect drug resistance are

:

• • • • • • • • A history of previously treated TB in a person presenting with active TB High community rates of drug resistant TB Positive HIV status High likelihood of exposure to nosocomial, prison or community sources of MDR-TB The infected person is from a country with a high MDR-TB rates Contacts with persons with MDR-TB Infected person has received inadequate treatment regimens for >2 weeks Smears or cultures remain positive despite 2 months of treatment for TB /fli6«o Ifo/f]u sfo{qmd National Tuberculosis Center

• • • • • • • •

Symptoms of Dr-TB is no different from ordinary TB

Cough (usually productive and maybe bloody) Low-grade fever Sweating Chills at night Fatigue Malaise Anorexia Shortness of breath • • • Weight loss Dull, aching chest pain or tightness Symptoms of extrapulmonary TB depend on the organ system involved but may include systemic symptoms.

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Early identification and prompt treatment of DR-TB

• • • • Prevents the spread of disease, Helps stop development of further amplification of resistance, Reduces the progression to permanent lung damage, and Results in higher cure rates.

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Thank You

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